Recurrent Nfrepmediated Nf1 Microdeletions

An estimated (50-60%) of constitutional NF1 microdeletions have a common recurrent 1.4-Mb deletion that includes NF1 and at least 13 other genes (Fig. 1; Table 2) (11). Both centromeric and telomeric deletion breakpoints cluster within two LCR sequences, or paralogs, termed NF1-REP-P1 and NF1-REP-M (Fig. 1). The direct orientation of these two NF1-REPs suggested a mechanism consistent with the existing paradigm whereby deletions occur by nonallelic homologous recombination, or paralogous recombination, between misaligned paralogs on the interchromosomal, intrachromosomal, or intrachromatidal level (22). For NF1, this mechanism was confirmed by mapping NF1-REP-mediated deletion breakpoints at the nucleotide level (17,23) and by haplotype analyses (16).

NF1-REPs are complex assemblies of paralogs from different sequence families consisting of expressed genes, pseudogenes, gene fragments, and non-coding sequence (Fig. 2) (24). NF1-REP-P1 and NF1-REP-M share a 51-kb segment of 97.5% sequence identity, termed NF1-REP-51, which serves as the substrate for paralogous recombination events. Two other components of the NF1-REP family include NF1-REP-P2, which is centromeric to NF1, and NF1-REP-E19 located on chromosome 19p13.13 (Fig. 2) (24,25). NF1 microdeletions owing to apparent paralogous recombination between NF1-REP-P2 and -M have been reported, but their breakpoints have not been mapped at the nucleotide level (26). Large kilobase-sized polymorphisms have not been observed in the NF1-REPs, although certain structural features, such as the inverted repeats in KIAA0563rel-y of NF1-REP-P1 that could mediate an inversion event, may generate such polymorphisms in the general population. There is no evidence of constitutional or somatic chromosomal translocations that could be attributable to recombina-

<-17cen

17q11.2

17qter

<-17cen

10 S

10 S

17q11.2

17qter

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